Unraveling Gene Fusions for Drug Repositioning in High-Risk Neuroblastoma.
Unraveling Gene Fusions for Drug Repositioning in High-Risk Neuroblastoma.
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DOI：
10.3389/fphar.2021.608778
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发表时间：
2021
影响因子：
5.6
通讯作者：
Tong W
中科院分区：
文献类型：
--
作者：
Liu Z;Chen X;Roberts R;Huang R;Mikailov M;Tong W
高危神经母细胞瘤(NB)仍然是当前儿童肿瘤患者面临的重大治疗挑战。基因融合等结构变异在加强对NB的机制理解和提高存活率方面显示出初步的前景。在这项研究中，我们对基因融合对高危NB患者的患者分层和治疗开发的翻译能力进行了全面的电子研究。具体地说，三种最先进的基因融合检测算法，包括ChimeraScan，SOAPfuse，和tophat-Fusion，被用来在498名神经母细胞瘤患者的RNA-SEQ数据集中识别融合转录本。然后，根据基因融合图谱，176名高危患者进一步分为四个不同的亚组。此外，还进行了Kaplan-Meier生存分析，提取了重新定义的高危人群的差异表达基因(Deg)并进行了功能分析。最后，通过Lincs L1000连接图中的药物转录图谱，在每个患者亚组中丰富了重新定位候选对象。我们发现，已发现的基因融合数量从临床低风险阶段增加到高风险阶段。尽管融合检测算法的技术一致性不是最优的，但它们在受干扰的通路和调节的deg方面具有相似的生物学相关性。基因融合谱可以用来重新定义具有显著发病年龄的高危患者亚组，从而产生改善的生存曲线(Log-rankp值≤0.05)。在48个重新定位的候选富集物中，45个(93.8%)具有抗肿瘤活性，24个(50%)被正在进行的临床试验或文献报道证实。基因融合谱对重新定义高危NB患者亚群具有辨别能力，并促进基于精确医学的药物重新定位实施。
High-risk neuroblastoma (NB) remains a significant therapeutic challenge facing current pediatric oncology patients. Structural variants such as gene fusions have shown an initial promise in enhancing mechanistic understanding of NB and improving survival rates. In this study, we performed a comprehensive in silico investigation on the translational ability of gene fusions for patient stratification and treatment development for high-risk NB patients. Specifically, three state-of-the-art gene fusion detection algorithms, including ChimeraScan, SOAPfuse, and TopHat-Fusion, were employed to identify the fusion transcripts in a RNA-seq data set of 498 neuroblastoma patients. Then, the 176 high-risk patients were further stratified into four different subgroups based on gene fusion profiles. Furthermore, Kaplan-Meier survival analysis was performed, and differentially expressed genes (DEGs) for the redefined high-risk group were extracted and functionally analyzed. Finally, repositioning candidates were enriched in each patient subgroup with drug transcriptomic profiles from the LINCS L1000 Connectivity Map. We found the number of identified gene fusions was increased from clinical the low-risk stage to the high-risk stage. Although the technical concordance of fusion detection algorithms was suboptimal, they have a similar biological relevance concerning perturbed pathways and regulated DEGs. The gene fusion profiles could be utilized to redefine high-risk patient subgroups with significant onset age of NB, which yielded the improved survival curves (Log-rank p value ≤ 0.05). Out of 48 enriched repositioning candidates, 45 (93.8%) have antitumor potency, and 24 (50%) were confirmed with either on-going clinical trials or literature reports. The gene fusion profiles have a discrimination power for redefining patient subgroups in high-risk NB and facilitate precision medicine-based drug repositioning implementation.
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